Building and maintaining joints by exquisite local control of cell fate

Abstract

We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an “interzone” region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints.

Genome-wide analysis of facial skeletal regionalization in zebrafish

“…In the ventral-intermediate domain we uncovered specific expression of Fgf-binding proteins ( fgfbp2a and fgfbp2b), suggesting fine regulation of Fgf signaling in this domain. In the intermediate domain, we discovered two putative Bmp inhibitors ( fsta and ctgfb) with tightly restricted expression near the developing hyoid joint, consistent with prior data showing that complex regulation of Bmp signaling is important for joint specification (Salazar et al, 2016;Smeeton et al, 2017). In the dorsal domain, we uncovered selective expression of genes previously implicated in earlier neural crest and ectomesenchyme development, including a Snail transcription factor (snai1a) (LaBonne and Bronner-Fraser, 2000), cadherin 11 (cdh11) (McLennan et al, 2015), potassium channel tetramerization domain-containing 15a (kctd15a), which interacts with tfap2a (Zarelli and Dawid, 2013), and endosialin (cd248a) (Das and Crump, 2012); this signature is consistent with our previous findings that dorsal arch CNCCs differentiate later than other arch CNCCs (Barske et al, 2016).…”

Genome-Wide Analysis of Facial Regionalization in Zebrafish

“…In the ventral-intermediate domain, we uncovered specific expression of Fgf binding proteins (fgfbp2a and fgfbp2b), suggesting fine regulation of Fgf signaling in this domain. In the intermediate domain, we discovered two putative Bmp inhibitors with tightly restricted expression near the developing hyoid joint, consistent with prior data showing complex regulation of Bmp signaling being important for joint specification (Salazar et al, 2016;Smeeton et al, 2017). In the dorsal domain, we uncovered selective expression of genes previously implicated in earlier neural crest and ectomesenchyme development, including Snail transcription factor (snai1a) (LaBonne and Bronner-Fraser, 2000), Cadherin 11 (cdh11) (McLennan et al, 2015), potassium channel tetramerization domain-containing 15a (kctd15a), which interacts with tfap2a (Zarelli and Dawid, 2013), and endosialin (cd248a) (Das and Crump, 2012); this signature is consistent with our previous findings that dorsal arch CNCCs differentiate later than other arch CNCCs (Barske et al, 2016).…”

A zebrafish model of developmental joint dysplasia: Manipulating the larval mechanical environment to drive the malformation and recovery of joint shape

“…The zebrafish jaw joint, between the MC and Palatoquadrate, was the focus of this study. This joint is synovial and can develop osteoarthritis [38] and has all the key features of mammalian skeleton including articular cartilage, joint cavity, synovium, tendon and ligaments [39,40]. The zebrafish also has a growing array of genetic tools [41] and is amenable to live imaging making it ideal for longitudinal studies.…”